Field
The present invention relates to stereoselective hydrogenation and in particular to the diastereoselective hydrogenation of bicyclic alkenes using known and novel hydrogenation catalysts.
Description of Related Art
Heterogeneous hydrogenation of alkenes is a well-established technique. The mechanism of action of a metal catalyst supported on an inert solid is generally considered to occur through the absorption of hydrogen onto the catalyst metal surface and the subsequent approach of the carbon-carbon double bond to that surface giving rise to hydrogen addition across one side of the double bond. The planar structure of the alkene is transformed into the well-known tetragonal carbon structure, which may give rise to a particular set of chiral centre(s) depending upon the structure of the parent alkene. Metals used as catalyst are typically nickel, palladium, platinum or other precious metals (platinum group metals). Further review of the art can be found in Ertl G., Knoezinger H., Schueth F., Weitkamp J.—Handbook of Heterogeneous Catalysis, John Wiley & Sons Inc, 2008, ISBN: 978-3-527-31241-2. Should the parent alkene be prochiral, hydrogenation in the presence of a heterogeneous metal catalyst is expected to give rise to a racemic mixture of enantiomers. Asymmetric heterogeneous hydrogenation, i.e. providing stereoisomeric products in unequal amounts, using a solid metal catalyst, has not have found the same industrial development as its asymmetric homogeneous hydrogenation counterpart and other strategies such as the use of a chiral modifier (e.g. tartaric acid or cinchonidine derivatives) adsorbed on the metal surface or covalently linked to the solid support of the metal catalyst as described in Murzin D. Y. et all, Catalysis Reviews: Science and Engineering, 2005, 47:2, 175-256, or in Ding K., Uozumi Y.—Handbook of Asymmetric Heterogeneous Catalysis, John Wiley & Sons Inc, 2008, ISBN 978-3-527-31913-8 are preferred as the logical route to influence chiral reaction pathways.
In the case of an unsaturated substrate bearing an existing chirality, the newly formed chiral centre will generate a mixture of diastereoisomers. In the absence of thermodynamic or kinetic controls, or other structural influencing effects, the mixture of diastereoisomers is expected to be a 50/50 mixture.
In some cases a functional group on an unsaturated (i.e. alkene) substrate bearing, or not, existing chirality, will have an asymmetric inductive effect, resulting in the preferential formation of one diastereoisomer over the another. In Chemical Reviews, 1993, Vol. 93, 1307-1370, Hoveyda et al. describe several examples of directed heterogeneous hydrogenations where a functional group interacts with the metal surface of the catalyst, favouring the approach of the substrate to the catalyst by a specific side, and leading to the delivery of hydrogen to the unsaturation site in a syn fashion (with respect to the directing group). That disclosure provides that “the nature of the directing group, solvent, catalyst, support, and hydrogen pressure” influence the product. In the same paper, hydrogenations with homogeneous catalysts are also discussed, mostly on allylic or homoallylic substrates (cyclic or linear olefins). This method is based on the binding of hydrogen, the alkene unsaturation and the directing group to the metal centre of the catalyst, which is dependent on the electronic structure and configuration of the substrate, the metal and its ligands. Trial and error ‘fine tuning’ of the directing group (when possible), the catalyst and the reaction conditions is required to provide a good asymmetric induction through experiment. The high design flexibility of homogeneous metal catalysts allows for such fine tuning, but the end result can still prove expensive both in terms of catalyst and process costs (time, temperature, suitability for large scale use) when compared with standard commercial metal catalysts supported on an inert solid.
In Chemical Reviews 1999, 99, 1191-1223,A, Mengel et al. review the use in synthesis of reactions on olefins or carbonyls where the diastereoselectivity is induced by a remote stereocentre, and the different models used to predict their stereochemical outcomes, such as Cram's and Felkin-Anh's rules. Reactions involving an a-chiral double bond, i.e. 1,2-induction, are the most common and cover a broad range of chemistry such as nucleophilic additions, electrophilic additions, cycloadditions or radical reactions. Moving the chiral centre to the β-position of the reaction centre, i.e. 1,3-induction, often requires the use of a chelating agent. In that case, either the reaction centre and the chiral centre are tethered together and the reagent is delivered externally of the chelate or the reagent becomes part of the chelate itself. Most reactions described are limited to nucleophilic additions, including carbonyl reductions with a metal hydride where the carbonyl and the β-chiral centre with an alcohol or ether functional group are first complexed with a Lewis acid.
In Organic Letters, 2002, 1347-1350 by A. Bouzide (FIG. 1) described the use of magnesium bromide as a complexing agent to achieve the Pd-catalysed diastereoselective hydrogenation of Baylis-Hillman ˜-hydroxyester alkenes. The author found the reaction to require stoichiometric amount of a magnesium salt and to be highly dependent on the solvent (no selectivity with MeOH, increasing selectivity for toluene <THF<EtOAc<CH2Cl2). Furthermore, many of the reaction conditions being quite mild (atmospheric pressure of hydrogen, room temperature for 1 h 30) and not suitable for use on a commercial scale due to limitation on reaction control (i.e. inability to remove pressure to stop reaction and high precious metal use) make such methods difficult and expensive industrially (42 wt % Pd/C catalyst loading, 144 wt % or 1.5 mol equivalent MgBr2 loading with regards to substrate).
If the chiral centre responsible for the diastereomeric induction can be pre-existing to the hydrogenation reaction (and its configuration predetermined, as in all three above papers), it could also be formed in situ prior to the final reduction (e.g. when hydrogenating dienes). In the latter case the first (favoured) reduction to take place will provide a racemic mixture of a partially reduced intermediate, but the newly formed chiral centre could influence the formation of the second (final) one, resulting in a diastereoselective reaction.
In specific cases, when generating products with an internal plane of symmetry, such hydrogenation may give rise to a stereoisomers mixture containing a meso isomer. A meso isomer is a non-optically active member of a set of stereoisomers, wherein at least two of the stereoisomers are optically active. In consequence, whilst containing two or more chiral centres the meso isomer is itself not chiral. A meso compound structure is superposable on its mirror image i.e. all aspects of the objects coincide and a meso isomer it does not produce a “(+)” or “(−)” reading in polarimetry.
Whilst prior art approaches to stereoselective hydrogenation, such as illustrated above, can give high levels of selectivity they generally use complex and expensive methods requiring precursors that themselves require considerable synthesis and are generally only suitable for laboratory (gram) scale synthesis.
There remains a need for a means of influencing hydrogenation using the well-established transition metal catalysts such as nickel, palladium or platinum on readily available supports such as charcoal, which may use simple and readily available adjuncts or auxiliaries to prove stereoselective hydrogenation an industrial scale. Furthermore desired catalysts should allow the use of a simple experimental methodology (e.g. a one-pot reaction), with a simple work up (e.g. by simple filtration) such as to remove catalyst and auxiliaries from reaction product.
There is a need for new catalysts and alternative methods for the selective hydrogenation of double bonds to provide stereochemical bias in hydrogenated product. Such catalysts are required that are capable of being prepared and used on an industrial scale. Such catalysts having a simple composition or at least a simple and hence economic pathway to preparation are required. Such catalysts with high temperature stability would prove useful. Such catalysts more resistant to poisoning would also prove useful.
The present invention is directed to a means of selective hydrogenation for disturbing the balance away from a statistical mix of diastereoisomers produced in hydrogenation of alkene using a metal cataltyst.
There is a further need to provide improved or alternative modified catalysts for general use.
Documents considered relevant to the present invention as identified in the priority application include US 2013/0165697 which discloses a method for hydrogenating phenols to cyclic ketones by hydrogenation using a palladium on carbon catalyst treated with one of sodium carbonate, lithium carbonate, sodium acetate or lithium acetate.
More specifically, US 2013/0165697 application describes the use of alkali doped Pd/C catalyst(s) to selectively reduce phenol compounds to the corresponding ketones products, in good yield when using their solution in an alcohol solvent. All 17 examples described the use of a broad range of weakly basic alkali salts (either lithium, sodium, potassium as cation, and carbonate or acetate as anion). All these various salts can influence the reaction pathway, i.e. limit the formation of side-products and over-reduction to the cyclohexanol derivatives to provide a good yield of the ketone products. But none these alkali doping agents demonstrate any stereocontrol on the considered reaction nor is any particular pattern in their effectivity evident.

Scheme derived from G Neri and all, Applied Catalysis A: General 11(1994) 49-59 CN 101502800 discloses the use of a palladium on carbon with an alkaline metal or alkaline earth metal auxiliary catalytic component for synthesising alkyl cylohexanone from alkyl phenols. U.S. Pat. No. 6,015,927 discloses the use of a palladium on carbon catalyst with a borax auxiliary component for preparing cyclohexanone from phenols.
In view of the above there is a further need to provide improved or alternative modified catalysts for general use and in particular to influence the stereochemical pathway of hydrogenation.
Products of the hydrogenation process described herein find commercial application such as disclosed in U.S. Pat. No. 5,550,200 in relation to rubber manufacture. As such, relatively small percentage changes in diastereoselectivity can be commercially useful as a product with application on a large industrial scale.